CZ201533A3 - Method of isolating mixture of enantiomers - Google Patents

Abstract

Method for isolating the E1 and E2 optical isomers, forming an enantiomeric mixture, from a mixture of four optical isomers E1, E2, E3, E4, first separating the E3 and E4 enantiomeric mixture from the solution, and subsequently isolating the base E1 and E2 mixture in the mother liquors, wherein E1 is (1R, 2S) -1- (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbutan-2-ol E2 ( The 1S, 2R) -enantiomer of the same compound, E3 and R4 are (1R, 2R) and (1R, 2R) respectively. (1S, 2S) enantiomers.

Description

Field of technology

Method for isolating the enantiomeric mixture of the optical isomers E1 and E2 from a mixture of four optical isomers E1, E2, E3, E4, the enantiomeric mixture of E3 and E4 being first separated from the solution and then the E1 and E2 mixture is isolated in the mother liquors in the form of a base.

Prior art

- (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbutan-2-ol formula I

is a substance with two optical centers and there are four optical isomers thereof. Thus, one can distinguish (1S, 2S); (1R, 2R); (1S, 2R) and (1R, 2S) isomer 1- (6-bromo-2-methoxyquinolin-3-yl) -4 (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbutan-2- olu.

In another aspect, this mixture can be described as a mixture of two racemates differing in their physical properties. Thus, an E 1 racemic mixture of (1R, 2S) and (1S, 2R) enantiomers can be defined, which can be termed E1 and E2, and an E II racemic mixture of (1R, 2R) and (1S, 2S) enantiomers E3 and E4. These markings are further used throughout the description of the invention.

The basic patent WO 2004/011436 discloses the enantiomer (αS, βR) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-naphthalenyl-β-phenyl-3-quinolineethanol (E1) as a substance used to treatment of mycobacterial disorders, in particular for the treatment of disorders caused by pathogenic mycobacteria Mycobacterium (M.) tuberculosis, M. bovis, M.avium and M. marinum.

In the basic patent WO 2004/011436, the isolation of the E1 enantiomer from a mixture of the E1 diastereomer is performed by chiral chromatography.

In the first section of the description of the invention in process patent EP 1888604 B1, the isolation of optical isomers is carried out by crystallization, which is a more preferred method for the preparation of (αS, βR) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α- naphthalenyl-p-phenyl-3-quinolineethanol (E1) on a larger production scale compared to the chiral chromatography method.

A mixture of the four optical isomers is prepared in the same manner as in the basic patent. The obtained reaction mixture is composed of two racemic mixtures.

Isolation of E1 from a mixture of optical isomers is performed in patent EP 1888604 B1 by resolution with the chiral compound 4-hydroxydinaphtho [2,1-d: r, 2'-f] [1,3,2] dioxaphosphepin 4-oxide or its derivatives.

The process for this resolution comprises reacting a mixture comprising (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbutan-2-ol stereoisomers with said chiral resolving agent in a suitable solvent. This is followed by separation of the precipitated salt and its recrystallization or stirring in a suitable solvent. Finally, (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbutan-2-ol base is liberated from this salt.

Of the numerous derivatives, the chiral compound of the 4-hydroxydinaphtho [2, LD: l ', 2'-f] _{[l) 3)} 2] -dioxaphosphepin 4oxidu as is best shown (llbR) -4-hydroxydinaphtho [2, LD, l', 2 f) [1,3,2] dioxaphosphepin 4-oxide.

The most suitable solvent for the resolution of (αS, βR) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-p-phenyl-3-quinolineethanol from a mixture of optical isomers is a mixture of acetone and dimethyl sulfoxide.

One molar equivalent of the 4-hydroxydinaphtho [2,1-d: r, 2'-f] [1,3,2] dioxaphosphepine 4-oxide derivative is disclosed in the patent as the most suitable amount for the resolution of the stereoisomer (aS, pR) -6-bromo-α- [2 - (dimethylamino) ethyl] -2-methoxy-al-naphthalenyl-β-phenyl-3-quinolineethanol.

For good salt exclusion, the patent discloses inoculation of a reaction mixture of (aS, PR) -6-bromo-α [2- (dimethylamino) ethyl] -2-methoxy-al-naphthalenyl-β-phenyl-3-quinolineethanol salts * (11bR) -4-hydroxydinaphtho [2,1-d: r, 2'-f] [1,3,2] dioxaphosphepin 4-oxide.

Inoculation with this salt can be performed before and after the addition of the chiral compound 4-hydroxydinaphtho [2,1-d: r, 2'-f] [1,3,2] dioxaphosphepin 4-oxide.

The chiral compound 4-hydroxydinaphtho [2,1-d: 1 ', 2'-f] [1,3,2] dioxaphosphepin 4-oxide is added to a mixture of stereoisomers of (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbutan-2-ol in the form of a solution in a dipolar aprotic solvent, preferably in dimethyl sulfoxide.

Improvement of optical and chemical quality of (aS, pR) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol * 4-hydroxydinaphtho [2.1] salts -d: 1 ', 2 f] [1,3,2] dioxaphosphepin 4-oxide is carried out by recrystallization or mixing it as a suspension in acetone, Ν, Ν-dimethylformamide or a mixture of N, N-dimethylformamide with water or alcohol. , dimethyl sulfoxide or mixtures thereof with water or alcohol. The most suitable of these solvents or mixtures thereof is acetone.

Release of (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbutan-2-ol base from the salt with 4-hydroxydinaphtho [2,1-d: According to the process patent, r, 2'-f] [1,3,2] dioxaphosphepin 4-oxide is carried out by reacting a salt with a suitable base in a suitable organic solvent. Toluene or tetrahydrofuran can be used as the organic solvent, and toluene is more suitable. Suitable bases are carbonates (sodium or potassium), bicarbonates (sodium or potassium), phosphate and disodium phosphate. Potassium carbonate is listed as more suitable.

An increase in the purity of (aS, pR) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-al-naphthalenyl-P-phenyl-3-quinolineethanol base can be achieved by crystallization from a suitable solvent, for example toluene or ethanol. .

The second section of the disclosure provides an alternative isolation of E1 by resolution after reaction with (11bS) -4-hydroxydinaphtho [2,1-d: 1 ', 2'-f] [1,3,2] dioxaphosphepin 4-oxide. E1 is obtained from the mother liquor after separation of the precipitated E2 stereoisomer. The alternative isolation procedure is analogous to the procedure described in the first section of the description of the invention.

The document also relates to a process for the isolation of (αS, βR) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol (E1) where the starting mixture of four stereoisomers is

6-Bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-al-naphthalenyl-β-phenyl-3-quinolineethanol is prepared by reacting 3-benzyl-6-bromo-2-methoxyquinoline and (3-dimethylamino) - 1'-propionaphthone in the presence of lithium diisopropylamide at -70 ° C to -80 ° C in tetrahydrofuran.

A suitable acid, such as acetic acid, is added to the reaction mixture at reduced temperature (less than 0 ° C). The (aR, 3S) stereoisomer is isolated from a mixture of stereoisomers using the chiral compound 4-hydroxydinaphtho [2,1-d: 1 ', 2'-f] [1,3,2] dioxaphosphepin 4-oxide or derivatives thereof (for the procedure see first section document).

This procedure also used to enrich the mixture, i.e. to increase the content of the racemic mixture of (αS, βR) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-al-naphthalenyl-β-phenyl-3-quinolineethanol and (aR, pS) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-al-naphthalenylP-phenyl-3-quinolineethanol by removing the racemic mixture of (aR, PR) -6-bromo-α- [ 2- (dimethylamino) ethyl] -2-methoxy-α-naphthalenyl-β-phenyl-3-quinolineethanol and (αS, βS) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1- naphthalenyl-P-phenyl-3-quinolineethanol.

The starting mixture for this enrichment step is a reaction mixture to which a suitable acid (e.g. acetic acid) has been added.

The essence of the invention

The present invention relates to a process for the isolation of a mixture of enantiomers EI (1R, 2S) -1- (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbutan-2- ol (EI) and (1S, 2R) 1- (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbutan-2-ol ( E2) from a mixture of EI and EII, i.e. four optical isomers (E1; E2; E3 and E4), which consists in first separating the enantiomers E3 and E4 from the mixture and further processing the mother liquors so that they are isolated from them enantiomers E1 and E2.

In a preferred embodiment, the racemate E1 and E2 thus obtained is converted into salts with an organic or inorganic acid. Hydrochloric, hydrobromic, sulfuric, phosphoric, L-tartaric, DL-tartaric, D-tartaric, citric or oxalic acids can be used for such conversion. These salts are converted back to E1 and E2 after purification with an inorganic base.

Detailed description of the invention

A mixture containing four optical isomers is prepared, the synthesis being carried out in the same manner as in the basic patent WO 2004/011436 or EP 1888604 B1, by reaction

3-benzyl-6-bromo-2-methoxyquinoline and (3-dimethylamino) -1'-propionaphthone in the presence of lithium diisopropylamide. at -60 ° C to -80 ° C in a solvent selected from cyclic ether, preferably tetrahydrofuran.

Isolation of the enantiomeric mixture of E1 and E2 (EI) in basic form from a mixture of four optical isomers is accomplished by exposing the enantiomeric pair of E3 and E4 (EI) in a suitable solvent. The precipitate E II formed is separated by filtration, leaving a mixture of E1 and E2 enantiomers in the mother liquor, the content of which is significantly higher than that of E3 and E4.

Further enrichment of the content of enantiomers E1 and E2 with respect to the content of enantiomers E3 and E4 is carried out after concentration of the mother liquor by crystallization in a suitable solvent. Thus, the product can be obtained in the form of a base which contains a mixture of enantiomers E3 and E4 with a content of less than 3%. The chemical and optical purity of the product thus obtained can be increased by recrystallization from a suitable solvent. As used herein, the term suitable solvent is understood to mean a solvent which allows at least one crystal of the desired solid phase to be precipitated; thus a mixture of E3 and E4 in the first step, E1 and E2 after concentrating the mother liquors in the second step and finally E1 and E2 of higher purity in the third step.

A mixture of four optical isomers E1; E2; E3 and E4 are prepared by reacting 3-benzyl-6-bromo-2-methoxyquinoline and (3-dimethylamino) -1'-propionaphthone in the presence of lithium diisopropylamide. at -60 ° C to -80 ° C in a solvent selected from cyclic ether, preferably tetrahydrofuran. After adding water to the reaction mixture, the organic layer containing four optical isomers, (1R, 2S) -1- (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -2- (naphthalene-1), was separated. -y 1) -1-phenylbutan-2-ol (EI), (1S, 2R) -1- (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -2- (naphthalene-1 - yl) -1-phenylbutan-2-ol (E2), (1R, 2R) 1- (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl ) -1-phenylbutan-2-ol (E3) and (1S, 2S) -1- (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -phenylbutan-2-ol (E4).

This organic layer is partially concentrated and a precipitate containing the enantiomeric mixture E II in a high content relative to the enantiomeric mixture of E I is precipitated by crystallization at room temperature. The content of the enantiomeric mixture E I is in the range of 5-20%. The enantiomeric content of mixture E I is determined by liquid chromatography.

The precipitated mixture E II is separated by filtration and the mother liquor is further concentrated. Crystallization at 5-10 ° C precipitates a second portion of the enantiomeric mixture E II. This is filtered off and the mother liquor contains an enantiomeric mixture of EI in a high content relative to the enantiomeric mixture of mixture E II. The content of the enantiomeric mixture E II is in the range of 5-25%. The enantiomeric content of the EII mixture is determined by liquid chromatography.

The mother liquor enriched in the enantiomeric EI mixture is concentrated and a suitable solvent is added. The solvent may be a C 1 to C 4 alcohol, an ester, a dipolar aprotic or a cyclic ether. Most suitable are methanol-1-ol, isopropyl acetate, acetonitrile or 2-methyltetrahydrofuran. Addition of solvent precipitates a precipitate which is filtered off. A product with a low content of enantiomeric mixture E II is obtained and at the same time the chemical quality of said product is increased, as this process removes some by-products of the reaction and significantly reduces the content of some. A further increase in chemical purity can be achieved by recrystallization of the crude isolate. Alcohols, esters and cyclic ethers and mixtures thereof can be selected for recrystallization. Preferred solvents are propan-1-ol, propan-2-ol, ethyl acetate, isopropyl acetate,

2-methylterahydrofuran.

The mother liquor obtained by filtering off the separated enantiomeric mixture E II can also be treated as follows.

The present invention also relates to a process for the isolation of enantiomeric mixtures of E I (E1, E2) in high chemical and optical purity by the formation of salts of the individual optical isomers.

A mixture of all four optical isomers of E1; E2; E3 and E4 are again prepared by reacting 3-benzyl-6-bromo-2-methoxyquinoline and (3-dimethylamino) -1'-propionaphthone in the presence of lithium diisopropylamide. at -60 ° C to -80 ° C in a solvent selected from cyclic ether, preferably tetrahydrofuran. After adding water to the reaction mixture, the organic layer containing the four optical isomers mentioned above was separated.

The organic layer was concentrated and crystallized at room temperature to precipitate an enantiomeric mixture of EII, which was collected by filtration.

The mother liquor contains a solution of the E I enantiomers in a solvent used as the reaction medium selected from cyclic ethers, preferably 2-methyltetrahydrofuran or tetrahydrofuran.

The enantiomeric content of the E II mixture in the mother liquor obtained is usually in the range of up to 25%. The content of substances is determined by liquid chromatography.

To this solution of enantiomers E I is added an inorganic or organic acid dissolved in water or a suitable organic solvent. The preferred organic solvent is ethanol, acetonitrile, tetrahydrofuran or 2-methyltetrahydrofuran.

Hydrochloric acid, sulfuric acid, phosphoric acid, L-tartaric acid, DL-tartaric acid, D-tartaric acid, citric acid and oxalic acid can be used to form salts of the E1 and E2 enantiomers.

The salt thus prepared contains a very small amount of the salt of the E II enantiomers, usually less than 1%.

Recrystallization of the E I enantiomer salt in a suitable solvent gives a product with a EII enantiomeric mixture content of less than 0.15%.

Examples of suitable solvents are C1 to C4 alcohol, isopropyl acetate, ethyl methyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran

The content of EII enantiomers in the crystallized substance is determined by liquid chromatography. The base is liberated from the salts of the E1 and E2 enantiomers by extraction with a suitable organic solvent and an aqueous solution of an inorganic base.

For example, 2-methyltetrahydrofuran or toluene and an aqueous solution of inorganic carbonates or bicarbonates can be used for the extraction.

2-Methyltetrahydrofuran and sodium carbonate appear to be most suitable.

The thus purified base of the mixture of enantiomers E I can be used for the preparation of (1R, 2S) Bedaquilin in a quality suitable for pharmaceutical purposes. The optical isomer (1R, 2S) of Bedaquilin is precipitated as a solid after crystallization of the E1s enantiomers with a suitable chiral acid in a suitable solvent. Recrystallization in a suitable solvent gives the product in satisfactory chemical and optical purity. Alcohols, cyclic ethers and dipolar aprotic solvents and mixtures thereof can be selected for recrystallization.

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Experimental part (A)

Preparation of a mixture of enantiomers of (6-bromo-2-methoxyquinolin-3-yl) -4 - ( ^, dimethylamino) -2 (naphthalen-1-yl) -1-phenylbutan-2-ol

In an apparatus under an inert atmosphere, a solution of lithium diisopropylamide (0.05 mol) as a 2 molar solution in a mixture of tetrahydrofuran, heptane, ethylbenzene was added to tetrahydrofuran (20 ml) cooled to -50 to -60 ° C. The mixture was cooled to -65 to -75 ° C and a solution was added

3-Benzyl-6-bromo-2-methoxyquinoline (0.0314 mol) in tetrahydrofuran (17 ml) for 10-20 minutes. The mixture is stirred at -65 to -70 ° C for 30 to 60 minutes. A solution of (3-dimethylamino) -1'-propionaphthone (0.0352 mol) in tetrahydrofuran (17 ml) was then added to this mixture over 15-30 minutes. The reaction mixture is stirred at -65 to -70 ° C for 30 to 150 minutes. After this time, water (100 mL) was slowly added dropwise to the reaction mixture. 2-Methyltetrahydrofuran (35 ml) was added to the mixture, and the mixture was stirred for 30 minutes. The formed organic layer was separated. Additional 2-methyltetrahydrofuran (45 mL) was added, the organic layer was shaken with brine and separated.

(B)

Isolation of a mixture of enantiomers of (1R, 2S) -1- (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -

2- (naphthalen-1-yl-1-phenylbutan-2-ol (EI) and (1S, 2R) -1- (6-bromo-2-methoxyquinolin-3-yl) -4 (dimethylamino) -2- ( naphthalen-1-yl) -1-phenylbutan-2-ol (E2) (1)

The organic layer obtained according to (A) is partially concentrated and the mixture is allowed to crystallize at room temperature for 17 hours and the precipitate is filtered off with suction and washed with 2-methyltetrahydrofuran.

A solid having a composition of 80% enantiomers E3 + E4.0.5% enantiomers E1 + E2 is obtained. The mother liquor is further concentrated and allowed to crystallize at 5-10 ° C. A precipitate forms which is filtered off with suction.

A solid with a composition of 76% enantiomers E3 + E4, 5% enantiomers E1 + E2 is obtained

The mother liquor is concentrated and isopropyl acetate is added. The precipitate formed is filtered off with suction and washed with solvent.

It gives a product with a composition of 7% enantiomers E3 + E4, 85% enantiomers E1 + E2

Yield: 6.5 g (37.3%) (2)

The organic layer obtained according to (A) was concentrated, acetonitrile (100 ml) was added, and the mixture was brought to a boil. A suspension of solid is formed, which is filtered off with suction while hot.

The filtered solid is washed with acetonitrile and dried. Its composition: 85% enantiomers E3 + E4, 1.2% enantiomers E1 + E2

After cooling to room temperature, a precipitate forms from the mother liquor, which is filtered off with suction and washed with solvent.

A product with a composition of 6% enantiomers E3 + E4, 82% enantiomers E1 + E2 is obtained

Yield: 2.1 g (12%)

The second mother liquor was concentrated, ethanol-heptane 1: 1 (20 mL) was added, and the mixture was stirred at room temperature. The precipitate formed is filtered off with suction and washed with solvent.

A product with a composition of 17% enantiomers E3 + E4, 71% enantiomers E1 + E2 is obtained. Yield: 0.9 g (5%)

Preparation of salts of enantiomers of (1R, 2S) -1- (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -2 (naphthalen-1-yl) -1-phenylbutan-2-ol (E1) and 1S, 2R) -1- (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbutan-2-ol (Έ2)

The organic layer obtained according to (A) is used to prepare salts of enantiomers.

This is processed according to B1 or B2.

A product enriched in the E1 and E2 enantiomers is used to prepare the salts

General procedure for the preparation of salts of enantiomers E1 and E2

The enriched product is dissolved in tetrahydrofuran at 40-50 ° C. After cooling to 30 ° C, an acid solution was added to the solution. The precipitate formed is stirred at room temperature for 2-3 hours. The precipitate is filtered off with suction, washed and dried.

If a precipitate does not precipitate at room temperature, the mixture is cooled to below 0 ° C.

Preparation of hydrochloride of E1 + E2 enantiomers

6.4 g of starting base (content of enantiomers E3 + E4: 24%) are dissolved in tetrahydrofuran (45 ml) under boiling. To a solution cooled to 30 ° C was added 1 equivalent of 1.25 M hydrogen chloride in ethanol. The mixture is stirred at room temperature for 2 hours and the precipitate formed is filtered off with suction. After washing with tetrahydrofuran, the precipitate is dried.

Yield: 5.0 g (73.3%)

HPLC: 97% content of E1 + E2 enantiomers, 1.9% content of E3 + E4 enantiomers

Preparation of oxalate of E1 + E2 enantiomers

220 mg of starting base (enantiomeric content E3 + E4: 17%) were dissolved in tetrahydrofuran (1.5 ml) at reflux. A solution of oxalic acid dihydrate (1 equivalent) in methanol was added to the mixture. The solution is cooled to -10 [deg.] C. and the precipitate formed is filtered off with suction. After washing with tetrahydrofuran, the precipitate is dried.

Yield: 160 g (59%)

HPLC: 95% content of E1 + E2 enantiomers, 0.8% content of E3 + E4 enantiomers

Claims (12)

Patent claims A process for isolating the enantiomeric mixture of the optical isomers E1 and E2 from a mixture of four optical isomers E1, E2, E3, E4, characterized in that the enantiomeric mixture of E3 and E4 is first separated from the solution and then the mixture E1 and E4 is isolated in the mother liquors. E2 in the form of a base, wherein E1 is (1R, 2S) -1- (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbutane- 2-ol E2 (1S, 2R) -enantiomer of the same substance, E3 and E4 are (1R, 2R) resp. (1S, 2S) enantiomers. Process according to Claim 1, characterized in that the mixture of E1 and E2 in the form of a base is further converted into salts, purified in this form and subsequently converted back into the base. Process according to Claim 1 or 2, characterized in that the E3 and E4 isomers are separated from a solution of the four optical isomers in a cyclic ether. Process according to claim 3, characterized in that the cyclic ethers are selected from tetrahydrofuran or 2-methylterahydrofuran or a mixture of both said cyclic ethers. Process according to Claim 4, characterized in that the solid bases of the E1 and E2 isomers in a mixture thereof are separated from the mother liquor obtained by separating the E3 and E4 isomers after the addition of a further solvent. Process according to claim 5, characterized in that the further solvent is selected from esters selected from isopropyl acetate, ethyl acetate or methanol alcohols, C6-C8 hydrocarbons, acetonitrile or mixtures thereof. Process according to Claim 6, characterized in that the separation is carried out at a temperature of -15 to + 20 ° C. Process for the preparation of a salt of isomers E1 and E2 according to claim 2, characterized in that the mixture of E1 E2 base is converted into salts in tetrahydrofuran or 2-methyltetrahydrofuran or in a mixture thereof by adding an inorganic or organic acid in water or in an organic solvent. Preparation process according to Claim 8, characterized in that the inorganic or organic acid is chosen from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, L-tartaric acid, DL-tartaric acid, D-tartaric acid, citric acid, oxalic acid. Preparation process according to Claim 9, characterized in that the preparation of the salt of isomers E1 and E2 is carried out at a temperature of -15 to + 20 ° C. Process according to any one of claims 8 to 10, characterized in that a base is liberated from a mixture of salts of the optical isomers E1 and E2 using an organic solvent selected from 2MeTHF, toluene, ethyl methyl ketone, isobutyl methyl ketone, butan-1-ol and a base selected from inorganic carbonates, bicarbonates, hydroxides, phosphates, hydrogen phosphates and dihydrogen phosphates A salt of formula B * HA, wherein B is a mixture of optical isomers E1 and E2 wherein E1 is (1R, 2S) -1- (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -2- (naphthalene -1-yl) -1-phenylbutan-2-ol and the E2 (1S, 2R) -enantiomer of the same substance and HA is an acid selected from HCl, HBr, H2SO4, H3PO4, L-tartaric, DL-tartaric, D-tartaric, lemon .. Annotation Title: Method for isolation of a mixture of enantiomers A process for isolating the enantiomeric mixture of the optical isomers E1 and E2 from a mixture of four optical isomers E1, E2, E3, E4, the enantiomeric mixture of E3 and E4 being first separated from the solution and then the mixture of E1 and E2 is isolated in the mother liquors in the form of a base. wherein E1 is (1R, 2S) -1- (6-bromo-2-methoxyquinolin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbutan-2-ol E2 ( 1S, 2R) -enantiomer of the same substance, E3 and E4 are (1R, 2R) resp. (1S, 2S) enantiomers.